A 64-year-old woman admitted with recurrent episodes of loss of consciousness and seizures. Glycemia and ECG were normal, while hypocalcemia was noted. Clinical history revealed carpo-pedal spasm since the age of 30 years, cognitive impairment, hypothyroidism since early adulthood, and menopause at 30 years. The clinical diagnosis of Pseudohypoparathyroidism type 1A was confirmed by molecular analysis, which demonstrated the heterozygous c.568_571del mutation of the GNAS gene.
A 64-year-old woman was admitted to the Neurological Unit of our hospital for recent recurrent episodes of loss of consciousness and seizures. Glycemia and ECG were normal, while hypocalcemia was present.
She has a normal brother and both her parents died in old age; her mother had cognitive impairment. Her clinical history evidenced carpo-pedal spasm since the age of 30 years, cognitive impairment, hypothyroidism diagnosed in early adulthood, spontaneous menarche, and oligomenorrhea followed by amenorrhea at the age of 30, which was diagnosed as precocious menopause. She was unmarried and had no pregnancy. She underwent bilateral hip arthroprosthesis at 45 and 50 years of age.
She was taking oral calcium (600 mg daily) and cholecalciferol (400 IU daily) for chronic hypocalcemia, diagnosed about 30 years earlier. She was also on therapy with perindopril for hypertension, atorvastatin for hypercholesterolemia, and L-thyroxine.
Physical examination revealed short stature (145 cm), slight overweight: 52 Kg (BMI: 25 Kg/m2), round facies, enlarged base of the nose, and brachydactyly. Her blood chemistry evidenced hypocalcemia (7.7 mg/dl, n.v. 8.2-10.2) with increased PTH levels (169 pg/ml, n.v. 15-65 pg/ml, intact PTH immunoassay), moderate 25OH vitamin D deficiency (22 ng/ml; n.v. ≥ 30), normal creatinine (1 mg/dl), and albumin (3.9 g/dl).
Brain computed tomography (CT) revealed calcifications of the basal ganglia, the cortical and subcortical white matter, and the cerebellum (dentate nuclei); subcutaneous pericranial ectopic calcifications were also present. Hand radiography confirmed shortness of the metacarpal bones and scapho-trapezoidal fusion (not shown). Bone mineral density of the spine and femoral bone was normal. Abdominal ultrasonography did not reveal kidney stones. The clinical picture was suggestive of PHP1A.
The patient was therefore promptly switched to 1,25 (OH)2 vitamin D (calcitriol 0.75 mcg daily, in 3 split doses) associated with oral calcium supplementation (1000 mg daily in 2 split doses, after lunch and dinner), with normalization of calcemia (9.2 mg/dl) and a decrease in PTH level (36 pg/ml). Serum phosphate was normal on therapy (4.3 mg/dl), while 24-hour urinary calcium on therapy was above the normal range (321 mg/24 h, n.v. <4 mg/kg/body weight); we do not have a clear explanation for this, since urinary calcium excretion is not normally increased in this condition.
However, a laboratory assay pitfall or an incorrect urine collection by the patient cannot be ruled out. A further urinary calcium control one month later, however, proved normal (200 mg/24 h). In addition, therapy with levetiracetam (1000 mg daily in 2 split doses) was started, and no further seizures or muscle spasms occurred.
The patient and her family underwent a genetic counseling session and gave informed consent to genetic analysis. Mutation analysis of the GNAS gene was performed on DNA extracted from a blood sample by means of Sanger sequencing and MLPA according to standard methods. The analyses revealed a heterozygous c.568_571del (p.Asp190Metfs13) frameshift mutation. The combination of physical, biochemical, and genetic findings led to the diagnosis of PHP1A.
FT4 and TSH levels were normal during substitutive treatment with L-tiroxine (75 mcg daily). Anti-thyroperoxidase and anti-thyroglobulin antibodies were negative and thyroid ultrasonography was normal, suggesting that TSH resistance was the cause of her hypothyroidism.
LH and FSH levels were in the menopausal range (FSH: 47 mU/ml, LH: 26 mU/ml); the history of premature menopause, however, was suggestive of the development of progressive LH and FSH resistance. Prolactin, basal cortisol, and ACTH levels were in the normal range. Basal growth hormone was 0.63 ng/ml, with IGF-1 levels (129 ng/ml) in the normal range for age. Calcitonin levels were increased (range: 44-92 pg/ml, n.v. <10 pg/ml) (she was not taking any proton-pump inhibitor), while carcinoembryonic antigen (CEA) was normal. Abdominal ultrasonography was normal, as were chest-X-ray and mammography. Our interpretation is that calcitonin resistance was also present, as part of the patient’s multi-hormonal resistance due to impairment of the cAMP activation pathway.
Six months later, during follow-up evaluation, the patient’s calcium level was seen to have increased to 10.6 mg/dl and PTH had decreased to 32 pg/ml; oral calcium supplementation was gradually reduced and then discontinued, and calcitriol was reduced to 0.25 mcg twice daily; subsequent controls revealed normal calcium (10 mg/dl) and slightly increased PTH (72 pg/ml) levels. She had no further loss of consciousness or seizures; on neurological examinations, levetiracetam treatment was confirmed, also on account of the frailty of the patient.